Glutamate activates ionotropic glutamate receptors (iGluRs) that mediate fast synaptic transmission, and metabotropic glutamate receptors (mGluRs) that modulate cell excitability. The iGluRs gate extracellular sodium and calcium entry into the cell, while the Group I mGluRs (1, 5) lead to the release of calcium from intracellular stores. Brain injury such as stroke or ischemia leads to increased extracellular glutamate, uncontrolled activation of iGluRs and mGluRs, and the toxic accumulation of intracellular calcium that is an essential initiator of cell death. Thus therapeutic strategies for the treatment of brain ischemia have focused on the use of iGluR and Group I mGluR antagonists. While iGluR antagonists are neuroprotective in modeled ischemia studies, likely due to inhibition of intracellular calcium accumulation, these compounds have failed in clinical trials. Similarly, Group I mGluR antagonists are neuroprotective in modeled ischemia studies, likely due to inhibition of intracellular calcium accumulation, yet delivery of most mGluR-selective compounds to the brain is difficult. We have begun to explore alternative neuroprotective strategies for brain ischemia using proteomics to identify novel proteins or peptides that modulate Group I mGluR signaling via interactions at the pharmacologically accessible extracellular amino terminal domain. Our first proteomic studies focused on the Group I mGluR subtype, mGluRS, and revealed a novel interaction with a recently cloned extracellular protein that promotes cell survival, ADNP (activity-dependent neuroprotective protein). ADNP contains an eight amino acid peptide sequence (NAPVSIPQ; NAP) that was shown to be the smallest active element of ADNP that can induce neuroprotection. Preclinical experiments show that NAP has potent neuroprotective, memory enhancing and neurotrophic properties. However, the mechanisms that underlie neuroprotection by NAP or ADNP are not known. Our preliminary data suggest that one mechanism of neuroprotection by NAP and ADNP is to regulate Group I mGluR signaling. The research studies proposed herein are important because 1) they begin to delineate the mechanisms of neuroprotection by NAP, an exogenous peptide, and ADNP, an endogenous protein, 2) they provide evidence for the novel regulation of mGluR signaling by peptide or protein interactions at the extracellular domain, and 3) they offer new approaches for therapeutic intervention in brain ischemia.